Abstract For chronic diseases such as hypertension, a lifelong treatment may be needed, but antihypertensive medications approved by the Food and Drug Administration (FDA) and their clinical treatment recommendations are often based on findings from randomized clinical trials (RCTs) lasting only a few years. Clearly, longer follow-up data are needed to monitor both long-term benefits and harms (side effects or adverse events). Post-trial follow-up of ALLHAT (Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial) participants was accomplished by linking trial data with Medicare data from 2002 to 2006. Several studies used these 4-year post-trial data to examine the risk of mortality, heart failure (HF), stroke, and hip and pelvic fractures. However, the 4-year post- trial period was short. It is still unknown if any effects arise or persist over the next 10 years or beyond. In particular, the risks of some long-term side effects associated with these antihypertensive drugs are unknown and have never been addressed in both the in-trial and the post-trial periods. Furthermore, no study has been conducted to incorporate the post-trial use of antihypertensive medications. Medicare Part-D comprehensive drug coverage was implemented in 2006 for the first time in Medicare history, making it possible to monitor the use of these medications. Therefore, we propose to address these many unanswered research questions by linking the data of ALLHAT participants with their Medicare data up to 2016, making the total follow-up time to 22 years (including 8-year in-trial and 14-year post-trial follow-up). We will address the following specific aims: 1) to explore patterns (types and frequency) of using antihypertensive medications during the post-trial period from Medicare Part-D data by examining if patients continued or changed their initial types of antihypertensive medications from 2007 to 2016; and to determine whether post-trial antihypertensive drugs affect or modify observed morbidity benefits and side effects associated with 3 trial treatments (diuretics, angiotensin-converting enzyme [ACE] inhibitors, and calcium channel blockers); 2) to determine the risks of developing long-term expected and unexpected side effects in patients receiving diuretics as compared to those receiving other antihypertensive drugs while taking into consideration death as a competing risk and adjusting for post-trial antihypertensive medication usage; 3) to quantify the risk and frequency of hospitalizations and emergency service utilizations for primary outcomes (cardiovascular disease [CVD] or stroke) and side effects in those 3 treatment arms while controlling for comorbidity; and 4) to compare the risk of long-term overall mortality, CVD- specific mortality, and other causes of death in patients receiving diuretics as compared to those receiving other drugs while adjusting for post-trial antihypertensive medications and comorbidity.